There are multiple mechanisms by which bacteria elicit an inflammatory response at mucosal sites;however, a pathway mediated by neuropeptides has received little attention but may be equally as important in the induction of the inflammatory response by bacteria. Neuropeptides such as substance P are released by sensory C type fiber nerves upon stimulation and bind to the neurokinin-1 receptor resulting in vasodilatation, plasma extravasation, and up-regulation of VCAM-1 and ICAM-1 on endothelial cells. Substance P may directly stimulate immune and epithelial cells via the neurokinin-1 receptor, causing the release of proinflammatory cytokines and IFN-? and activation of NF-?B. Chemotactic factors produced as a result of substance P release recruit neutrophils, monocytes, macrophages, and lymphocytes to the local site. Interestingly, the neurokinin-1 receptor is found on many essential cells of the host immune response, including T and B cells, macrophages, dendritic cells, PMNs, mast cells, and natural killer cells. Thus, substance P may be important for the induction of the innate immune response and the initiation of the adaptive response. In order to investigate a role for the neurogenic inflammatory response in bacterial infection at a mucosal site, mice will be infected in the genital tract with Chlamydia muridarum, a natural parasite of mice and a strict mucosal pathogen, infecting only the superficial epithelial layer of the genital tract, including the cervix, endometrium, and oviduct. Chlamydial infection elicits a strong acute inflammatory response which not only is responsible for the pathologic response but is also necessary to control the infection until the adaptive immune response is activated. Ultimately, a Th1 response is required for resolution of the infection and resistance to reinfection. To date there have been no studies on the role of the neurogenic inflammatory response in either the male or female genital tracts. In preliminary experiments a marked reduction in the acute inflammatory response of mice lacking substance P in the first 24 hours following chlamydial infection was observed as well as a decrease in the production of several important chemokines and cytokines, indicating that substance P may play a role in both the innate and adaptive immune responses in the genital mucosa. Thus, it is hypothesized that the neurogenic inflammatory response is essential for both the induction of the acute inflammatory response and is required for the production of a protective T cell response against bacterial infection in the genital mucosa. The focus of this proposal will be to characterize the effects of neuropeptides in the genital mucosal site on the development of the acute inflammatory response and its role in eliciting the protective cell-mediated immune response using chlamydial genital infection as a model. The Specific Aims will be 1) to determine the role of the neurogenic inflammatory response on the initiation of the innate immune response to chlamydial genital infection;2) to determine the effect of the neuropeptides on the course and pathogenesis of chlamydial genital infection;and 3) to determine if the neurogenic inflammatory pathway affects immunity to reinfection in the genital tract. Virtually all mucosal sites have a network of neural sensory fibers which release neuropeptides upon stimulation of the nerves. It has been well known that these molecules can initiate an inflammatory response, but their role in bacterial infections at mucosal surfaces has not been addressed to a great extent. There has been no work on the role of neuropeptides in the female genital mucosa in the response to infection with sexually- transmitted bacteria. Thus, this proposal will determine the contribution of neuropeptides to genital tract immunity and disease and may lead to the description of a new paradigm in our understanding of the balance of resistance versus disease in the genital tract.